Effect of Accessory Renal Arteries on Essential Hypertension and Related Mechanisms.

BACKGROUND: This case-control study aimed to determine whether there were differences between patients with essential hypertension with accessory renal arteries (ARAs) and those without ARAs. METHODS AND RESULTS: The enrolled patients with essential hypertension were divided into the ARA group (n=200) and control group without ARAs (n=238). After propensity matching, 394 patients (197 in each of the 2 groups), were included. The 24-hour BP (4.33/2.43 mm Hg) and daytime BP (4.48/2.61 mm Hg) of patients in the ARA group were significantly higher than those of the control group (P<0.05). The flow-mediated dilation was lower in the ARA group (5.98±2.70 versus 5.18±2.66; P<0.05). In correlation analysis, the horizontal plasma aldosterone concentration had the highest correlation with 24-hour, daytime, and nighttime systolic BP (r=0.263, 0.247, and 0.243, respectively; P<0.05) and diastolic BP (r=0.325, 0.298, and 0.317, respectively; P<0.05). As for multivariate regression analysis, plasma aldosterone concentration was a significant risk factor for elevated 24-hour, daytime, and nighttime systolic BP (ß=0.249 [95% CI, 0.150-0.349], 0.228 [95% CI, 0.128-0.329], and 0.282 [95% CI, 0.187-0.377], respectively; P<0.05) and elevated diastolic BP (ß=0.289 [95% CI, 0.192-0.385], 0.256 [95% CI, 0.158-0.353], and 0.335 [95% CI, 0.243-0.427], respectively; P<0.05). Direct renin concentration was also a risk factor for 24-hour and daytime BPs, whereas heart rate was a risk factor correlated with 24-hour, daytime, and nighttime diastolic BP (all P<0.05). For the mixed-effects model for repeated measures, the results were similar to results of the multivariate regression analysis (all P<0.05). CONCLUSIONS: ARAs could contribute a higher BP of patients with essential hypertension and might promote the development of essential hypertension. The mechanism might be related to overactivation of the renin-angiotensin-aldosterone system and sympathetic nervous system.

Development and validation of prognostic nomogram for T1-3N0M0 non-small cell lung cancer after curative resection.

BACKGROUND: Radical resection plus lymph node dissection is a common treatment for patients with T1-3N0M0 non-small cell lung cancer (NSCLC). Few models predicted the survival outcomes of these patients. This study aimed to developed a nomogram for predicting their overall survival (OS). MATERIALS AND METHODS: This study involved 3002 patients with T1-3N0M0 NSCLC after curative resection between January 1999 and October 2013. 1525 Patients from Sun Yat-sen University Cancer Center were randomly allocated to training cohort and internal validation cohort in a ratio of 7:3. 1477 patients from ten institutions were recruited as external validation cohort. A nomogram was constructed based on the training cohort and validated by internal and external validation cohort to predict the OS of these patients. The accuracy and practicability were tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). RESULTS: Age, sex, histological classification, pathological T stage, and HI standard were independent factors for OS and were included in our nomogram. The C-index of the nomogram for OS estimates were 0.671 (95% CI, 0.637-0.705),0.632 (95% CI, 0.581-0.683), and 0.645 (95% CI, 0.617-0.673) in the training cohorts, internal validation cohorts, and external validation cohort, respectively. The calibration plots and DCA for predictions of OS were in excellent agreement. An online version of the nomogram was built for convenient clinical practice. CONCLUSIONS: Our nomogram can predict the OS of patients with T1-3N0M0 NSCLC after curative resection. The online version of our nomogram offer opportunities for fast personalized risk stratification and prognosis prediction in clinical practice.

Development and validation of a nomogram for predicting survival time and making treatment decisions for clinical stage IA NSCLC based on the SEER database.

Background: The aim of this study was to establish and validate a nomogram model for accurate prediction of patients' survival with T1aN0M0 none small cell lung cancer (NSCLC). Methods: The patients, diagnosed with the stage IA NSCLC from 2004-2015, were identified from the Surveillance, Epidemiology and End Results (SEER) database. The variables with a P-value < 0.05 in a multivariate Cox regression were selected to establish the nomogram. The discriminative ability of the model was evaluated by the concordance index (C-index). The proximity of the nomogram prediction to the actual risk was depicted by a calibration plot. The clinical usefulness was estimated by the decision curve analysis (DCA). Survival curves were made with Kaplan-Meier method and compared by Log-Rank test. Results: Eight variables, including treatment, age, sex, race, marriage, tumor size, histology, and grade were selected to develop the nomogram model by univariate and multivariate cox regression. The C-index was 0.704 (95% CI, 0.694-0.714) in the training set and 0.713 (95% CI, 0.697-0.728) in the test set, which performed significantly better than 8th edition AJCC TNM stage system (0.550, 95% CI, 0.408-0.683, P < 0.001). The calibration curve showed that the prediction ability of 3-years and 5-years survival rate demonstrated a high degree of agreement between the nomogram model and the actual observation. The DCA curves also proved that the nomogram-assisted decisions could improve patient outcomes. Conclusion: We established and validated a prognostic nomogram to predict 3-years and 5-years overall survival in stage IA NSCLC.

A standard for hilar and intrapulmonary lymph node dissection and pathological examination in early non-small cell lung cancer.

BACKGROUND: There is considerable variation in the staging of lymph nodes (LNs) as part of tumor, node, metastasis (TNM) staging of non-small cell lung cancer (NSCLC). A new dissection and pathological examination standard for hilar and intrapulmonary LNs needs to be established for patients with early-stage T1-3N0M0 NSCLC. METHODS: This study involved 3,002 patients with T1-3N0M0 NSCLC who underwent radical lobectomy or total pneumonectomy in the thoracic departments of 11 Chinese institutions between January 1999 and October 2013. The Cox model was applied for univariate and multivariate analyses in the examination of station 10, 11 LN and station 12, 13, 14 LN. A hilar and intrapulmonary standard (HI standard) was then established based on univariate and multiple-factor analyses conducted using the Cox model. RESULTS: Among the 3,002 patients enrolled in the study, 2,609 underwent at least one examination of station 10, 11 LN (A1), while 393 did not undergo examination of station 10, 11 LN (A0). The A0 and A1 groups had 5-year survival rates of 76% and 80%, respectively (P=0.018). Further, 1,764 patients underwent at least one examination of station 12, 13, 14 LN (B1), while 1,238 patients did not (B0). The B0 and B1 groups had 5-year survival rates of 77% and 82%, respectively (P=0.008). In total, 1,269 patients attained the HI standard (C1), and 1,733 did not (C0). The C0 and C1 groups had 5-year survival rates of 77% and 83%, respectively (P<0.001). CONCLUSIONS: The HI standard can improve both the prognosis and survival rates of patients with T1-3N0M0 NSCLC. This will provide important guidance for pulmonary LN dissection and pathological examination in NSCLC cases.

Knockdown of Ran GTPase expression inhibits the proliferation and migration of breast cancer cells.

Breast cancer is the second leading cause of cancer­associated mortality in women worldwide. Strong evidence has suggested that Ran, which is a small GTP binding protein involved in the transport of RNA and protein across the nucleus, may be a key cellular protein involved in the metastatic progression of cancer. The present study investigated Ran gene expression in breast cancer tissue samples obtained from 140 patients who had undergone surgical resection for breast cancer. Western blot analysis of Ran in breast cancer tissues and paired adjacent normal tissues showed that expression of Ran was significantly increased in breast cancer tissues. Immunohistochemistry analyses conducted on formalin­fixed paraffin­embedded breast cancer tissue sections revealed that Ran expression was associated with tumor histological grade, nerve invasion and metastasis, vascular metastasis and Ki­67 expression (a marker of cell proliferation). Kaplan­Meier survival analysis showed that increased Ran expression in patients with breast cancer was positively associated with a poor survival prognosis. Furthermore, in vitro experiments demonstrated that highly migratory MDA­MB­231 cancer cells treated with Ran­si­RNA (si­Ran), which knocked down expression of Ran, exhibited decreased motility in trans­well migration and wound healing assays. Cell cycle analysis of Ran knocked down MDA­MB­231 cells implicated Ran in cell cycle arrest and the inhibition of proliferation. Furthermore, a starvation and re­feeding (CCK­8) assay was performed, which indicated that Ran regulated breast cancer cell proliferation. Taken together, the results provide strong in vitro evidence of the involvement of Ran in the progression of breast cancer and suggest that it could have high potential as a therapeutic target and/or marker of disease.

Suppression of Kpnß1 expression inhibits human breast cancer cell proliferation by abrogating nuclear transport of Her2.

Breast cancer (BC) is one of the most fatal diseases and poses critical health problems worldwide. However, its mechanisms remain unclear. Consequently, there is an urgency to investigate the mechanisms involved in BC initiation and progression and identify novel therapeutics for its prevention and treatment. In this study, we identified karyopherin ß-1 (Kpnß1) as a possible novel therapeutic target for BC. Western blotting was used to evaluate the expression of Kpnß1 in four pairs of tumorous and adjacent non-tumorous tissues. The results revealed that the protein level of Kpnß1 was higher in the cancer samples compared with those in the corresponding normal samples. Immunohistochemistry was performed on 140 BC cases and indicated that Kpnß1 was significantly associated with clinical pathological variables. Kaplan-Meier curve revealed that high expression of Kpnß1 was related to poor BC patient prognosis. A starvation and re-feeding assay was used to imitate the cell cycle using the SKBR-3 cell line, indicating that Kpnß1 plays a critical role in cell proliferation. The Cell Counting Kit-8 assay revealed that SKBR-3 cells treated with Kpnß1-siRNA (siKpnß1) grew more slowly than the control cells, while flow cytometry revealed that low-Kpnß1 expressing SKBR-3 cells exhibited increased BC cell apoptosis. Furthermore, the interaction between Kpnß1 and Her2 was clearly observed by immunoprecipitation, indicating that Kpnß1-knockdown abrogated nuclear transport of Her2. In summary, our findings revealed that Kpnß1 is involved in the progression of BC and may be a useful therapeutic target.

PFTK1 regulates cell proliferation, migration and invasion in epithelial ovarian cancer.

PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine-protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development.

Nucleostemin promotes the proliferation of human glioma via Wnt/ß-Catenin pathway.

Nucleostemin, nucleolar guanosine triphosphate (GTP)-binding protein 3, is a member of the MMR1/HSR1 GTP-binding protein family. The important roles of nucleostemin in self-renewal, cell cycle regulation, apoptosis, and cell proliferation of various cancer types as been shown. Nevertheless, its expression and potential functions in human glioma is still unclear. In the present study, we demonstrated that up-regulation of nucleostemin was tightly related to poor 5-year-survival ratios. In serum-starved and re-feeding models of U251 and U373MG, we observed the rising expression of nucleostemin and p-ß-Catenin (p-Tyr645) were accompanied with cell proliferation markers (cyclin D1 and proliferating cell nuclear antigen (PCNA)). Employing nucleostemin-depletion models, we found down-regulated nucleostemin and p-ß-Catenin. The flow cytometry analysis proved the weakened cell proliferation. Moreover, we detected the translocation of ß-Catenin into the nucleus was impaired, meaning the inhibition of the Wnt/ß-Catenin pathway. Taken together, we identified a positive correlation between up-regulation of nucleostemin and human glioma cell proliferation and that knocking-down nucleostemin alleviated glioma proliferation by reducing ß-Catenin transportation into the nucleus. All results suggested that nucleostemin might accelerate human glioma proliferation via the Wnt/ß-Catenin pathway.

Downregulation of ubiquitin-specific protease 14 (USP14) inhibits breast cancer cell proliferation and metastasis, but promotes apoptosis.

Breast cancer is the second leading cause of cancer-related death in women. Previously, evidence suggested that ubiquitin-specific protease 14 (USP14) was associated with various signal transduction pathways and tumourigenesis. In this study, we demonstrate that USP14 is a novel therapeutic target in breast cancer. A Western blot analysis of USP14 was performed using seven breast cancer tissues and paired adjacent normal tissues and showed that the expression of USP14 was increased in the breast cancer tissues. Immunohistochemistry was conducted on formalin-fixed paraffin-embedded sections of breast cancer samples from 100 cases. Using Pearson's χ(2) test, it was demonstrated that USP14 expression was associated with the histological grade, lymph node status and Ki-67 expression in the tumour. The Kaplan-Meier analysis revealed that increased USP14 expression in patients with breast cancer was associated with a poorer prognosis. In in vitro experiments, the highly migratory MDA-MB-231 cells that were treated with USP14-shRNA (shUSP14) exhibited decreased motility using Transwell migration assays. Next, we employed a starvation and re-feeding assay, and the CCK-8 assay demonstrated that USP14 regulated breast cancer cell proliferation. Furthermore, we used flow cytometry to analyse cellular apoptosis following USP14 knockdown. Taken together, our results suggested that USP14 was involved in the progression of breast cancer.